BACKGROUND AND CHALLENGES
Primary brain cancers pose immense challenges for effective treatment. The most common form of brain cancer in adults is glioblastoma, which originates from glial cells, the non-neural supportive cells in the brain. Glioblastoma is extremely aggressive. Malignant tumor cells readily invade and migrate locally and blend with neighboring normal brain tissue, causing damage to critical neural functions and often leading to lethal tumor recurrence. In the U.S. in 2015,an estimat 22,850 new cases of primary cancers in the brain or nervous system wl be diagnosed, and more than 15,000 lives are expected to be lost to brain cancer this year.
Fortunately, the death rate from primary brain cancers has decreased somewhat over the past three decades in the U. S., thanks to progress made in the treatment of this disease. Still, only about one out of every three patients with primary brain cancer will survive longer than five years after initial diagnosis. Further improvement in survival rates for brain cancer patients requires more effective therapies.
Recognizing the urgency of the situation facing brain cancer patients, the National Foundation for Cancer Research funds leading cancer researchers who are seeking a deeper understanding of the molecular mechanisms of brain cancers, with a special emphasis on translating these research discoveries into new, and hopefully more effective, therapies for these patients. Below are four examples of the innovative brain cancer research programs that the National Foundation for Cancer Research currently supports.
TRANSLATING RESEARCH INTO THERAPY
Molecular Imaging, the next generation of highly sensitive imaging technology
Research has shown that brain cancer cells tend to over-produce certain "combinations" of cancer-causing molecules or biomarkers on their cell surface that, together, cause the early progression of abnormal cell growth. NFCR supported scientist James Basilion, Ph.D., is developing the next generation of highly sensitive imaging technology - called molecular imaging-that may produce a visual record of the collection of these early biomarkers on the whole surface of a very small tumor.
To image multiple biomarkers on the whole surface of a living tumor, the Basilion team at Case Western Reserve University has generated a powerful reporter probe, known as Beta Gal. The scientists have engineered Beta Gal to bind to biomarkers on living cancer cells and immediately generate a signal that "reports" the presence of the biomarkers, creating an image that can be captured by a camera.
This platform technology has the potential to enable doctors to detect brain and many other cancers at their earliest stage. What's more, it will provide clinicians with improved accuracy compared to existing detection methods which only sample small areas of tumors from biopsy and thus tend to yield only partial information. This unique advantage of molecular imaging holds great promise for the detection of brain cancer and other types of cancer - at their earliest stage - when patients can be most effectively treated.
Discovery of brain tumor's escape path - a new mechanism for treatment
NFCR supported scientist, Webster K. Cavenee, Ph.D., at Ludwig Institute for Cancer Research, and his team previously identified EGFRvIII, a variant version of EGFR (Epidermal Growth Factor Receptor), that is commonly present in tumor cells in aggressive brain cancer, glioblastoma. EGFR-targeting therapies against this growth factor are initially effective but patients develop resistance as the glioblastomas escape these "smart drugs", allowing tumors to grow again.
Recently Dr. Cavenee and his team used state-of-the-art microarray technology to identify a unique gene in glioma cells called KLHDC8A or SΔE1. This gene may produce the molecule that enables the gliomas to escape the attack of EGFR-targeting drugs and continue to grow through an alternative molecular pathway. Dr. Cavenee reasons that this gene may be used as a new target to overcome the resistance developed by glioablastomas. NFCR and Dr. Cavenee are working together to develop innovative therapies that combine traditional EGFR-targeted drugs with newly developed approaches to block glioblastoma's escape pathway and reduce tumor survivability, giving patients a better chance against this lethal brain cancer.
Developing new anti-cancer drugs that target only cancer cells
NFCR supported scientist Alan Sartorelli, Ph.D., is a world-renowned pharmacologist who designs, synthesizes, and evaluates novel anti-cancer drugs. He and his team at Yale University developed laromustine, a promising drug for treating brain tumors, leukemia, lung and other types of cancer. Dr. Sartorelli's team is now developing a second generation of laromustine-like agents that will have enhanced treatment effects.
Laromustine belongs to a class of chemotherapy agents called guanine O6-targetingÂ drugs which modify specific molecules in the DNA of cancer and other rapidly dividing normal cells, leading to cell death. Dr. Sartorelli's team is now developing a second generation of laromustine-like agents that only target cancer cells. The team has designed an inactive form of the drug that converts to the active, cell-killing form only after it enters a cancer cell; this conversion process does not take place in normal, healthy cells. In addition, the drug's unique conversion mechanism may also allow targeting of metastatic cancer cells that have spread to distant sites in the body. With his innovative drug design, Dr. Sartorelli envisions that these new targeted drugs will cause little toxicity while effectively treating patients whose tumors are resistant to existing therapies.
Biomarkers of tumor resistance to anti-angiogenic therapy
Vascular endothelial growth factor (VEGF) is used by tumors to make new blood vessels to supply blood and nutrients for tumor growth - a process called angiogenesis. Anti-angiogenic therapy blocks the VEGF pathway and aims to starve tumors of nutrients and oxygen and stop their growth. This therapy is available for glioblastoma patients but the results are only short-lived: although some patients may initially respond well to this treatment approach, in all cases, the tumors eventually re-grow. Identification of cell molecules or biomarkers that indicate tumor progression during anti-angiogenic therapy is urgently needed to guide the development of new treatments that will stop the growth of glioblastoma.
World-renowned NFCR supported scientist, Rakesh K. Jain, Ph.D., at Massachusetts General Hospital, previously illuminated the cancer research community on biomarkers of anti-angiogenic therapy in colorectal cancer. Recently his team identified, for the first time, two molecular biomarkers that are present at high levels in glioblastoma cells after patients have undergone anti-angiogenic therapy. These biomarkers may drive the tumor to progress, causing resistance to therapy. Dr. Jain is working tirelessly to confirm these intriguing findings and explore other potential molecular mechanisms of treatment resistance. Dr. Jain and his collaborators, a team of leaders in the field of clinical oncology and new therapy development for brain cancer patients, have several ongoing clinical trials that treat glioblastoma patients with the newest targeted therapies. NFCR is proud to support Dr. Rakesh Jain, a leader we know can answer these critical questions in brain tumor anti-angiogenic therapy and lead the research community to develop new and more powerful treatments for this deadly cancer.
NEXT STEPS: HOW CAN YOU HELP
These research projects hold great promise for developing more effective therapies for brain cancer. With more money, however, they could ramp up their efforts and accelerate progress - and that is what the urgent plight of glioblastoma patients demands. Your contribution will be directed to these and other life-saving NFCR research initiatives against brain cancer. To donate, click here.